Pharmacological analysis of the mode of interaction of McN-A-343 at atrial muscarinic M2 receptors.
The mode of interaction of the muscarinic M2 receptor partial agonist, McN-A-343 (4-(m-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium), was investigated in the electrically-driven guinea-pig left atrium. Comparison of the negative inotropic responses to this agent with those of the full agonist, carbachol, followed by operational model-fitting, yielded estimates of the dissociation constant (KA) and efficacy (tau) of McN-A-343. Following partial receptor inactivation with propylbenzylcholine mustard, the properties of McN-A-343 as an inhibitor of the carbachol-mediated responses were assessed. Analysis of the data, according to both competitive and allosteric models of interaction, favored the former model. The log KB of McN-A-343 as an antagonist was - 4.65+/-0.06, and was not significantly different from the log KA of this agent as an agonist.
Christopoulos
A
A
Department of Pharmaceutical Biology and Pharmacology, Victorian College of Pharmacy (Monash University), Parkville, Australia. christo@lenti.med.umn.edu
Mitchelson
F
F
D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000494:pharmacology*; D000494:Allosteric Regulation; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism
D018721:Muscarinic Agonists; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride